Time-Limited Venetoclax-Based Combos Improve PFS Outcomes in Treatment-Naïve CLL

Time-limited targeted therapy with venetoclax plus obinutuzumab with or without ibrutinib demonstrated superior progression-free survival outcomes compared with standard chemoimmunotherapy in patients with chronic lymphocytic leukemia.

Time-limited targeted therapy with venetoclax (Venclexta) plus obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) demonstrated superior progression-free survival (PFS) outcomes compared with standard chemoimmunotherapy in patients with chronic lymphocytic leukemia (CLL). A marked benefit was reported among those with unmutated IGHV status, according to data from an interim analysis of the phase 3 GAIA/CLL13 trial (NCT02950051) presented at the 2022 EHA Congress.1,2

At a follow-up of 38.8 months, the median PFS was not reached with venetoclax/obinutuzumab/ibrutinib (GIV) or venetoclax/obinutuzumab (GV). Compared with standard chemoimmunotherapy (median PFS, 52 months), GIV reduced the risk of progression by 68% (HR, 0.32; 97.5% CI, 0.19-0.54; P < .000001) and GV reduced the risk of progression by 58% (HR, 0.42; 97.5% CI, 0.26-0.68; P < .0001).

The 3-year PFS rates were 90.5% and 87.7% for patients who received GIV (n = 231) and GV (n = 229) respectively, compared with 75.5% for those who received standard chemoimmunotherapy (n = 229).

For patients who were randomly assigned to receive venetoclax plus rituximab (Rituxan; RV) the median PFS was 52.3 months and did not meet statistical significance (HR, 0.79; 97.5% CI, 0.53-1.18; P = .183). The 3-year PFS rate in the RV arm (n = 237) was 80.8%.

These data support previously reported findings of increased minimal residual disease (MRD) negativity rates among patients treated in the experimental arms of GAIA. MRD negativity has prognostic value as a marker for improved PFS.3

“The interim PFS analysis [shows] the triplet combination of venetoclax and obinutuzumab plus ibrutinib was clearly superior to chemoimmunotherapy with FCR [fludarabine, cyclophosphamide, rituximab] for the younger patients or BR [bendamustine plus rituximab] for the elderly patients who were fit with a hazard ratio of 0.32 and venetoclax/obinutuzumab therapy was clearly superior was a hazard ratio of 0.42,” said Barbara Eichhorst, MD, an associate professor and attending physician at the University Hospital Cologne in Cologne, Germany, in a presentation of the data.“Venetoclax plus rituximab was not superior, so it depends on the antibody, which you combine to the venetoclax treatment.”

Investigators also presented data from a subgroup analysis of patients with IGHV-mutant disease.

“Prognosis was favorable for patients with mutated IGHV status, there's not a big difference between chemoimmunotherapy and the targeted agents," Eichhorst said. "However, we see a huge difference particularly for patients with unmutated IGVH status."

The 3-year PFS rate for those in the GIV arm (n = 101) was 96.0%; this rate was 93.6% for patients who received GV (n = 89), 87.0% for those who received RV (n = 95), and 89.9% for those who received chemoimmunotherapy (n = 95).

For those with unmutated IGHV status, the 3-year PFS rates were 86.6%, 82.9%, and 76.4%, for those who received GIV (n = 123), GV (n = 130), and RV (n = 134), respectively, compared with 65.5% with standard therapy (n = 131).1

Investigators initiated GAIA to evaluate time-limited, chemotherapy-free treatment options to challenge the standard of care for treatment-naïve patients with CLL selected by a fitness score.

“For elderly or unfit patients, we have the option between targeted treatments including long-term treatment with BTK nhibitors as well as time-limited treatment with the BCL-2 inhibitor venetoclax, in combination with obinutuzumab, the latter based on data from the CLL14 trial [NCT02242942],” Eichhorst said. “We did not yet have data from a randomized phase 3 trial for the fit patients on venetoclax plus obinutuzumab, therefore, we treat those patients [in Europe] and many countries with chemoimmunotherapy when they have a favorable IGVH status, or with continuous treatment with BTK inhibitors.”

The design randomly assigned eligible participants to 1 of 4 arms: standard chemoimmunotherapy, or time-limited RV, GV, or GIV.2 Individuals with detected del(17p) or TP53 mutations or Richter transformation were not permitted per study protocol. Additionally, patients were required to have normal creatine clearance (≥ 70 ml/min) and a cumulative incidence rating scale (CIRS) score of no greater than 6.1,2

The primary outcome measures were minimal residual disease (MRD) negativity rate in peripheral blood, defined as 10-4, between the GV arm and the standard chemoimmunotherapy arm, and PFS for the GIV arm vs the standard therapy arm.2

Six cycles of the experimental therapy were administered to patients in GAIA. Patients in the RV and GV arms received 6 additional cycles of venetoclax alone and patients in the GIV arm received 6 cycles of ibrutinib plus venetoclax.

A standard ramp-up approach was used for oral venetoclax from cycle 1 at 20 mg on days 22 to 28 of a 28-day cycle; 50 mg on days 1-7 followed by 100 mg on days 8 to 14, 200 mg on days 15 to 21 and 400 mg on days 22 to 28 of cycle 2; and 400 mg on days 1 to 28 of cycles 3-12.

Obinutuzumab was administered intravenously (IV) at 2 doses on day 1 of cycle 1 (100 mg on part 1 of day 1; 900 mg part 2 of day 1) and 1000 mg IV on days 8 and 15. For cycles 2 to 6, patients received obinutuzumab 1000 mg IV on day 1 of each cycle. Ibrutinib was administered 420 mg once daily for all cycles. Rituxumab was administered at 375 mg/m² IV on day 0 of cycle 1 and at 500 mg/m² on day 1 of cycles 2-6.

Those randomly assigned to the standard chemoimmunotherapy arm were treated with either fludarabine, cyclophosphamide, rituximab or bendamustine plus rituximab depending on age (65 years or younger vs older, respectively).2

Data presented at the 63rd American Hematology Association Annual Meeting and Exposition, at month 15 analysis, the study met the coprimary end point of MRD negativity in the peripheral blood. Specifically, the rate of undetectable MRD in the GV arm was 86.5% vs 52.0% in the chemoimmunotherapy arm (P < .0001). The MRD negativity rate was 92.2% in the GIV arm and was found to be significant compared with chemoimmunotherapy (P < .0001). The MRD rate in the RV arm was not statistically significant at 57.0%.3

In terms of safety, Eichhorst noted that there were no major differences in the incidence of grade 3 or higher events across the study arms at 81.5% with chemoimmunotherapy, 73.0% with RV, 84.2% with GV, and 83.5% with GIV. There were higher rates of grade 3 or higher infections in the GIV arm (22.1%) and the control arm (20.4%) compared with the RV (11.4%) and GV (14.9%) arms. Febrile neutropenia grade 3 or higher was also reported at a higher rate in the GIV (7.8%) and control arms (11.1%) compared with the RV (4.2%) and GV (3.8%) arms. 1

Other common grade 3 or higher AEs included blood and lymphatic system disorders reported in 56.5%, 43.5%, 56.1%, and 50.6% of patients in the control, RV, GV, and GIV arms, respectively.

In her concluding remarks Eichhorst noted that a direct comparison between GIV and GV from the GAIA trial is ongoing.1


  1. Eichhorst B, Niemann C, Kater A, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13 trial. Presented at: 2022 EHA Congress. June 9-17, 2022; Vienna, Austria. Abstract LB2365.
  2. Standard chemoimmunotherapy (FCR/BR) versus rituximab + venetoclax (RVe) versus obinutuzumab (GA101) + venetoclax (GVe) versus obinutuzumab + ibrutinib + venetoclax (GIVe) in fit patients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation (GAIA). Clinical Trials.gov. Updated September 30, 2021. Accessed June 11, 2022. https://clinicaltrials.gov/ct2/show/NCT02950051
  3. Eichhorst B, Niemann CU, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments (RVe, GVe, GIVe) vs standard chemoimmunotherapy (CIT: FCR/BR) in frontline chronic lymphocytic leukemia of fit patients: first co-primary endpoint analysis of the international intergroup GAIA (CLL13) trial. Blood. 2021;138(suppl 1):71. doi:10.1182/blood-2021-146161